Protein calorie malnutrition is a common complicating condition in patients with alcoholic chronic liver disease (Mendenhall et al. Am J Med 1984;76:211-222; Mendenhall et al. Am J Clin Nutr 1986;43:213-218) and non-alcoholic chronic liver disease (O'Keefe et al. Lancet 1980;2:615-617; Morgan et al. Gut 1976;17:113-118). Factors contributing to the high prevalence include poor dietary intake, elevated resting energy expenditure, and nutrient malabsorption (McCullough A J and Tavill A S. Seminars in Liver Disease 1991;11:265-277). Patients with end stage liver disease complicated by portal hypertension are particularly likely to be malnourished and, when hospitalized, frequently require active nutritional therapy. While the effects of malnutrition in chronic liver disease on fatty acid nutrition have not been extensively studied, because of an increased resting energy expenditure, fat malabsorption and abnormal fat catabolism, these patients may have significant abnormalities in fatty acid metabolism (Cabre et al. Am J Gastroent 1988;83:712-717; Palombo et al. Gastroenterology 1987;93: 1170-1177). One potential mechanism for such a disturbance would be an inadequate intake of essential fatty acids as part of the global protein calorie malnutrition.
Dietary fatty acids are classified according to their chain length. Long chain fatty acids contain 14 carbons or greater and can be further characterized by the number of double bonds contained in their structure into saturated, monounsaturated and polyunsaturated subgroups. The two fatty acids essential in human nutrition are linoleic acid and alpha-linolenic acid from which polyunsaturated fatty acids of the omega 6 series and omega 3 series are formed through enzymatic desaturation and elongation by the liver. The body cannot convert omega 3 fatty acids to omega 6 fatty acids or vice versa. Patients with advanced liver disease may have an impaired ability to form polyunsaturated fatty acids, including arachidonic and eicosapentaenoic acid, from their essential fatty acid precursors, potentially altering membrane composition and eicosanoid production.
It has now been demonstrated that there is a defect in elongation and desaturation in end stage liver disease, resulting in dramatically reduced levels of the polyunsaturated fatty acids such as arachidonic, eicosapentaenoic, and docosahexaenoic acid. Although there may be some degree of concurrent linoleic acid deficiency, the ratio of linoleic/arachidonate confirms that elongation and desaturation is the limiting factor. Arachidonic acid levels in tissue phospholipids are usually very tightly regulated, such that arachidonic acid levels are stable at varying levels of linoleic acid content in the diet. Only with essential (linoleic) fatty acid deficiency or with the consumption of omega 3 fatty acids in place of omega 6 fatty acids do arachidonic acid levels fall. Given the importance of arachidonic acid in second messenger metabolism, it is reasonable to suspect that some of the untoward side effects of end stage liver disease, including decreased immunocompetence and increased risk of infection and infectious mortality, may be a consequence of functional essential fatty acid deficiency. In the normal diet arachidonic acid is very low, because it is only found in any quantity in the membranes of animal flesh. To add arachidonic acid alone to a diet formulation is problematic, since arachidonic acid supplementation in normal individuals is pro-inflammatory and immunosuppressive. In the alternative, to give eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which provide benefits regarding immunosuppression, would likely lead to a worsening of arachidonic acid levels, and potentially essential fatty acid deficiency.
Thus a need still exists to develop a novel dietary formulation which can normalize membrane composition to accomplish two goals: (1) restore arachidonic acid levels to normal and reverse signs related to essential fatty acid deficiency, and (2) provide added immune-enhancing benefits of EPA and DHA.
Accordingly, an object of the invention is to provide a novel formulation which can restore arachidonic acid levels and which can increase immunity of a subject.
Another object of the invention is to provide a method of restoring arachidonic acid levels in a subject by administering the novel formulation of the invention.
Another object of the invention is to provide a method of increasing immunity or minimizing a risk of infection in a subject by administering the novel formulation of the invention.
Another object of the invention is to provide a method of treating essential fatty acid deficiency in a subject by administering the novel formulation of the invention.
A still further object of the invention is to provide a structured lipid which provides a high energy fat source and fatty acids which assist in fighting infection and treating essential fatty acid deficiency.
These and other objects and features of the invention will be apparent from the following description and from the claims.